CLINICAL ANDPATHOLOGICAL STUDIES IN THE OLDEST OLD In the next two decades, the numberof Americans aged 90 years and older will nearly double to over 3 million people. Because previous studies have few, if any, subjects over 90 years of age, little is known about these pioneers or about factors associated with successful aging and health in this group. The goals of this proposal are to investigate clinical,genetic, and pathological factors associated with extreme old age. We superimpose our investigations on the Leisure World Cohort Study, initiated in 1981. For over 20 years, cohort members (N=13,979) have provided medical history and lifestyle information including morbid conditions, family history, exercise, social activities, and medication use such as antioxidants and non-steroidal anti-inflammatorydrugs (NSAIDS). Our central hypothesis is that oxidative damage and inflammationin the brain results in aging, disease and death and that intake of antioxidants and NSAIDS will slow cognitive decline and improvethe health of the oldest old. Our Specific Aims are: (1) to examine factors associated with longevity in the 4,682 cohort members who reached age 90 compared to the 6734 who did not, (2) to determine the prevalence, incidence, and risk factors for dementia in 1,644 living cohort members in their tenth and eleventh decades, (3) to conduct longitudinal follow-up to measure rates of cognitive and functional decline in these oldest old subjects, and (4) to complete our investigations with clinical pathological correlates of brain aging in health and disease, focusing on the association of cerebral measures of oxidative injury, inflammatorymarkers, and plaqueand tangle pathology as it relates to clinical status and previous use of antioxidant and anti-inflammatorycompounds. The Leisure World Cohort Study provides a unique population sample for the study of genetic and environmental factors associated with longevity and successful aging in the oldest old. With a substantial cohort of committed subjects and 20 years of prospective data, our proposed investigations can contribute much to the understanding of cognition, functional abilities, and cerebral pathology in the oldest members of our society.